Lipidomics Screening of Celecoxib in ex Vivo Human Whole Blood Assay - Part B

NCT02413203 | Completed Results

• 1 other identifier: 818658-Part B
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Cardiovascular complications of NSAIDs, selective for inhibition of COX-2, stimulated interest in microsomal prostaglandin E synthase-1 (mPGES-1) as an alternative drug target. Global deletion of mPGES-1 in mice suppresses prostaglandin (PG) E2 and augments PGI2 by PGH2 substrate rediversion. Unlike COX-2 inhibition or gene deletion, mPGES-1 deletion does not cause a predisposition to thrombogenesis and hypertension. However, cell-specific deletion of mPGES-1 reveals that the predominant substrate rediversion product among the prostaglandins varies by cell type, complicating drug development. The research team has developed an ultra performance liquid chromatography/ tandem mass spectrometry (UPLC-MS/MS) technique that allows the quantification of a wide range of lipids beyond the prostaglandin pathway (leukotrienes, anandamide and the 2-arachidonylglycerol cascades). This study is designed to examine different pathway interventions from the arachidonic acid cascade by anti-inflammatory compounds (with a focus on mPGES-1 inhibition) in whole human blood in vitro (Part A) and ex vivo (Part B). In Part B, healthy volunteers will be asked to take a single, therapeutic dose of celecoxib and blood and urine samples will be collected before and after drug administration. Collected blood will be stimulated ex vivo, and lipids and their metabolites will be measured in blood and urine, respectively. The investigators expect that lipid profile from ex vivo hWBA done on celecoxib-treated subjects will recapitulate findings from the in vitro hWBA received with celecoxib-treated human blood (Part A).

Conditions

Healthy

Keywords

lipidomics; ex vivo human whole blood assay; celecoxib; selective COX-2 inhibitor

Outcome Measures

Primary Outcomes (4)

• Quantification of Plasma Lipids in the Whole Blood: Prostaglandin E2 (PGE2)

  PGE2 in blood taken from celecoxib-treated subjects and stimulated ex vivo with LPS was compared to similarly treated blood from placebo group. Plasma PGE2 was normalized to sample volume (ng/ml) and expressed as a percentage of subject's pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents PGE2 concentration in ng/ml.

  A single visit of around 4 hours

• Quantification of Plasma Lipids in the Whole Blood: Prostaglandin F2a (PGF2a)

  PGF2a in blood taken from celecoxib-treated subjects and stimulated ex vivo with LPS was compared to similarly treated blood from placebo group. Plasma PGF2a was normalized to sample volume (ng/ml) and expressed as a percentage of subject's pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents PGF2a concentration in ng/ml.

  A single visit of around 4 hours

• Quantification of Plasma Lipids in the Whole Blood: Thromboxane B2 (TxB2)

  TxB2 in blood taken from celecoxib-treated subjects and stimulated ex vivo with LPS was compared to similarly treated blood from placebo group. Plasma TxB2 was normalized to sample volume (ng/ml) and expressed as a percentage of subject's pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents TxB2 concentration in ng/ml.

  A single visit of around 4 hours

• Quantification of Plasma Lipids in the Whole Blood: 15-Hydroxyeicosatetraenoic Acid (15-HETE)

  15-HETE in blood taken from celecoxib-treated subjects and stimulated ex vivo with LPS was compared to similarly treated blood from placebo group. Plasma 15-HETE was normalized to sample volume (ng/ml) and expressed as a percentage of subject's pre-dose control using the formula: percentage of pre-dose control = (Cpost-dose/Cpre-dose) × 100%, where C represents 15-HETE concentration in ng/ml.

  A single visit of around 4 hours

Secondary Outcomes (4)

• Urinary Lipid Metabolites: PGE2 Metabolite (PGE-M)

  A single visit of around 4 hours

• Celecoxib Plasma Concentration

  A single visit of around 4 hours

• Urinary Lipid Metabolites: PGI2 Metabolite (PGI-M)

  A single visit of around 4 hours

• Urinary Lipid Metabolites: TxB2 Metabolite (Tx-M)

  A single visit of around 4 hours

Study Arms (2)

Celecoxib

EXPERIMENTAL

Oral administration of a single pill of celecoxib (200 mg). Celecoxib pills will be over-encapsulated to match the placebo.

Drug: Celecoxib

Placebo

PLACEBO COMPARATOR

Oral administration of a single placebo pill.

Drug: Placebo

Interventions

Celecoxib DRUG

Blood and urine collections before and 3 hours after celecoxib administration.

Also known as: Celebrex

Celecoxib

Placebo DRUG

Blood and urine collections before and 3 hours after placebo administration.

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age between 18 - 50
• Volunteers must be in good health as based on medical history
• All volunteers must be non-smoking and non-pregnant

You may not qualify if:

• Subjects with any medical condition, which according to the investigator, may interfere with interpretation of the study results, be indicative of an underlying disease state, or compromise the safety of a potential subject (cancer or history of significant cardiovascular disease (including stroke or TIA), renal, hepatic, gastrointestinal, respiratory, endocrine, metabolic, hematopoietic, or neurological disorders).
• Subjects who have received an experimental drug within 30 days prior to the study
• Subjects who have taken aspirin or aspirin containing products for at least two weeks prior to the study.
• Subjects who are sensitive or allergic to celecoxib (Celebrex) or its components
• Subjects who have taken any formulation of celecoxib including but not limited to Celebrex, Celebra, Onsenal for at least two weeks prior to the start of the study and throughout the study
• Subjects who have taken acetaminophen, NSAIDs, COX-2 inhibitors (OTC or prescription) for at least two weeks prior to the study.
• Subjects who are consuming any type of tobacco product(s).
• Subjects who consume high doses of antioxidant vitamins daily (vitamin C\> 1000mg, Vitamin E\> 400IU, Beta Carotene\> 1000IU, Vitamin A\> 5000IU, Selenium\> 200mcg, Folic Acid\> 1mg) for the two weeks prior to the start of the study and throughout the study.
• Subjects who consume alcohol, caffeine or high fat food 24 hours prior to the study.

Sponsors & Collaborators

• University of Pennsylvania: lead
• Eli Lilly and Company: collaborator

Study Sites (1)

The Clinical Translational Research Center (CTRC) at the Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Interventions

Celecoxib

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Garret A. FitzGerald
• Organization: Univesrity of Pennsylvania

garret@upenn.edu

215-898-1185

Study Officials

• Garret FitzGerald, MD

  University of Pennsylvania, Institute for Translationals Medicine and Therapeutics

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 19, 2015
• First Posted: April 9, 2015
• Study Start: March 1, 2015
• Primary Completion: November 1, 2015
• Study Completion: November 1, 2015
• Last Updated: May 30, 2017
• Results First Posted: May 30, 2017

Record last verified: 2017-04

Locations

US (1)